Supercritical water oxidation (SCWO) of penicillin (PCN) was investigated under different operating conditions. The chemical oxygen demand (COD) removal rate could reach 99.4% at 400 °C, 24MPa, 1min and oxidation coefficient (OC) of 2. Experimental results showed that COD removal had no significant dependence on temperature and pressure variations. By contrast, COD removal could be significantly promoted with OC increasing from 0 to 2.0, but the effect was negligible as the OC further increased; similarly, longer residence time than a definite value seemed to contribute little to COD removal. Initial and deeper degradation pathways of penicillin were proposed based on the reactive force field (ReaxFF) molecular dynamics (MD) simulations. By tracing the evolution of intermediates, the migration routes of S and N during the SCWO process were obtained with H2S and NO2 produced as the corresponding products. Simulation results showed that SCW and oxidant not only accelerated the degradation by producing highly reactive radicals or molecules, but also participated in reactions by serving as H and O sources. Moreover, catalysis of water clusters in C-heteroatom bond cleavage was also observed.